{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T10:44:10Z","timestamp":1763981050488,"version":"3.45.0"},"reference-count":43,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2025,11,15]],"date-time":"2025-11-15T00:00:00Z","timestamp":1763164800000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Inhibitors of 11\u03b2\u2010hydroxysteroid dehydrogenase type 1 (HSD\u20101), the pre\u2010receptor regulator of intracellular active glucocorticoid levels, have promise to treat glucocorticoid excess whether endogenous (neoplastic or physiological elevated cortisol) or iatrogenic (glucocorticoid medicine toxicity). Three structurally distinct HSD\u20101 inhibitors have shown tachyphylaxis of pharmacodynamic activity in adipose, a key target tissue, suggesting that the clinical utility of the class might be limited by that pharmacological phenomenon. To determine whether the potent inhibitor clofutriben also showed adipose tachyphylaxis, HSD\u20101 activity was measured during daily oral clofutriben administration and infusion of mass\u2010labeled enzyme substrate (cortisone) via microdialysis catheters placed in subcutaneous abdominal adipose of 12 persons with type 2 diabetes and obesity. During initial dosing, clofutriben was associated with dose\u2010dependent decreases of mass\u2010labeled HSD\u20101 product (cortisol) in adipose dialysate, from &lt;\u200925% at 1\u2009mg to &gt;\u200990% at 6\u201310\u2009mg. At steady state, all clofutriben doses were associated with &gt;\u200990% decreases of mass\u2010labeled cortisol in adipose dialysate with no evidence of tachyphylaxis. By surface plasmon resonance, clofutriben showed fast\u2010on, slow\u2010off (residence time 535\u2009s) binding to human HSD\u20101. Molecular docking revealed that clofutriben can form a ternary complex with nicotinamide\u2010adenine dinucleotide phosphate (NADPH) cofactor and the human HSD\u20101 active site. The higher activation energy to dissociate that trimolecular interaction, compared to a bimolecular drug\u2010enzyme interaction characteristic of other HSD\u20101 inhibitors, is posited to be responsible for the enzyme kinetic and favorable pharmacological properties of clofutriben.<\/jats:p>","DOI":"10.1111\/cts.70398","type":"journal-article","created":{"date-parts":[[2025,11,15]],"date-time":"2025-11-15T15:35:32Z","timestamp":1763220932000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Human Adipose Tissue 11\u03b2\u2010Hydroxysteroid Dehydrogenase Type 1 Inhibition Without Tachyphylaxis by Clofutriben, a Pseudo\u2010Irreversible Enzyme Inhibitor"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6498-7663","authenticated-orcid":false,"given":"Guohua","family":"An","sequence":"first","affiliation":[{"name":"University of Iowa  Iowa City Iowa USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julio A.","family":"Gutierrez","sequence":"additional","affiliation":[{"name":"Scripps Clinic  La Jolla California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0741-9579","authenticated-orcid":false,"given":"Cele","family":"Abad\u2010Zapatero","sequence":"additional","affiliation":[{"name":"University of Illinois  Chicago Illinois USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shin\u2010Kai","family":"Lin","sequence":"additional","affiliation":[{"name":"Eurofins Discovery  Taipei Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caleb","family":"Schmicker","sequence":"additional","affiliation":[{"name":"IQVIA Laboratories  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aimee","family":"Rinas","sequence":"additional","affiliation":[{"name":"IQVIA Laboratories  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian","family":"Engel","sequence":"additional","affiliation":[{"name":"IQVIA Laboratories  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tobias","family":"Magers","sequence":"additional","affiliation":[{"name":"IQVIA Laboratories  Indianapolis Indiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tonya K.","family":"Marmon","sequence":"additional","affiliation":[{"name":"Marmon Biostatistics  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4400-5669","authenticated-orcid":false,"given":"David A.","family":"Katz","sequence":"additional","affiliation":[{"name":"Sparrow Pharmaceuticals  Portland Oregon USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,11,15]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-1818"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1551"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-16-0946"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2011.09.009"},{"key":"e_1_2_9_6_1","unstructured":"A. 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